Molecularly targeted therapeutics represent a promising approach to cancer drug discovery1; examples include Gleevec (imatinib mesylate)2, and Herceptin (trastuzumab)3. A limitation of this approach is that some oncogenic proteins are not amenable to inhibition with a small molecule. For example, the RAS oncoproteins are implicated in the genesis of numerous human tumors, but have been difficult to target effectively with small molecules4. The first rat sarcoma (RAS) oncogene was discovered as a genetic element from the Harvey and Kirsten rat sarcoma viruses with the ability to immortalize mammalian cells45-47. Mutated RAS oncogenes (i.e. HRAS, NRAS and KRAS) are found in 10-20% of all human cancers: KRAS mutations are found in >90% of pancreatic cancers, 50% of colon cancers and 25% of lung adenocarcinomas; NRAS mutations are found in 30% of liver cancers and 15% of melanomas, and HRAS mutations are found in 10% of kidney and bladder cancers48. Mice with a KRASG12V knock-in allele develop bronchiolo-alveolar adenomas49-52; mice expressing KRASG12V and CDK4R24C develop sarcomas and pre-neoplastic lesions of the pancreas49.
RAS proteins are guanine-nucleotide-binding proteins with GTPase activity and are associated with the plasma membrane. In the GTP-bound form, RAS proteins are mitogenic. Mutation of glycine-12 to other amino acids (including valine, i.e. RASG12V) results in an oncogenic allele with constitutive mitogenic, transforming activity and reduced GTPase activity53. Four downstream pathways activated by RAS proteins are (i) the RAF/MEK/ERK pathway, which regulates cell-cycle progression, (ii) the PI3K/PDK/AKT pathway, which regulates cell survival, (iii) the RalGDS pathway, which regulates membrane trafficking and vesicle formation, and (iv) the PLC-gamma/PKC pathway, which regulates Ca++ signaling4, 53, 54. Small molecules that activate the GTPase activity of RAS proteins might also be developed, although such an approach may be challenging to realize4. Alternative approaches, such as inhibiting RAS lipidation and processing, have been pursued4, 13.
A complementary strategy involves searching broadly for oncogenic-RAS-selective lethal compounds that kill tumor cells only in the presence of oncogenic RAS5. This genotype-selective approach can be applied to oncogenes such as those of the RAS gene family, whose gene products cannot be easily inhibited by a small molecule drug12. Such oncogene-selective compounds may target novel proteins in oncoprotein-linked signaling networks. Compounds reported to display oncogene-dependent lethality include (1) the rapamycin analog CCI-779 in myeloma cells lacking PTEN6, (2) Gleevec in BCR-ABL-transformed cells7, and (3) other less well-characterized compounds8-11.
Therefore, there remains a need to identify compounds that selectively target and inhibit growth of tumor cells.